Mitochondrial Disease FAQ

Fact: Every 30 minutes a child is born who will develop a mitochondrial disease by the age of 10.

Mitochondria (plural for mitochondrion) are sometimes described as cellular “power plants” because among other things, mitochondria are responsible for creating more than 90% of the energy needed by the body to sustain life and support growth. In addition to making energy, mitochondria are also deeply involved in a variety of other activities, such as making steroid hormones and manufacturing the building blocks of DNA.

Given the fact that mitochondria are responsible for fueling nearly all of the body’s energy needs, there is a long list of symptoms depending on which organ or tissue is having the “energy crisis.” When symptoms arise from three or more organ systems a mitochondrial disease should definitely be considered.

4. How common are mitochondrial diseases?It is now said that mitochondrial diseases are nearly as common as childhood cancer! One in 4,000 children born in the United States every year will develop a mitochondrial disorder by age 10. In adults, many diseases of aging have been found to have defects of mitochondrial function. These include, but are not limited to, type 2 diabetes, Parkinson’s disease, atherosclerotic heart disease, stroke, Alzheimer’s disease, and cancer. In addition, many medicines can injure the mitochondria.

Different symptoms indicative of mitochondrial diseases may present over time. As patients begin to present with multiple catastrophic symptoms it can be hard for physicians to pinpoint the main cause. It is crucial that they never remove or set aside a symptom to try and diagnose the problem. All symptoms must be given consideration.

Mitochondrial disease should be suspected when: A “common disease” has atypical features that set it apart from the pack Three or more organ systems are involved. Recurrent setbacks or flare ups in a chronic disease occur with infections.

6. Is there a cure for mitochondrial diseases?There is not a cure for mitochondrial diseases. Doctors must look at each patient on a case-by-case basis and try to develop a treatment plan. Treatment may involve special diets and/or a combination of vitamins, and reducing any stress on the body.

-- If this gene trait is recessive (one gene from each parent), often no other family members appear to be affected. There is a 25 percent chance of the trait occurring in other siblings.— If this gene trait is dominant (a gene from either parent), the disease often occurs in other family members. There is a 50 percent chance of the trait occurring in other siblings. MtDNA (DNA contained in the mitochondria) inheritance.

— There is a 100 percent chance of the trait occurring in other siblings, since all mitochondria are inherited from the mother, although symptoms might be either more or less severe. Combination of mtDNA and nDNA defects:

— Relationship between nDNA and mtDNA and their correlation in mitochondrial formation is unknown Random occurrences

— Diseases specifically from deletions of large parts of the mitochondrial DNA molecule are usually sporadic without affecting other family members disease

The children are born and develop normally for a period of time in virtually every case. Symptoms begin between the first few weeks of life and about 25 years of age. Two-thirds of the cases begin to show symptoms of seizures, or episodic loss of developmental milestones, within the first 2 years of life. The liver disease is often subclinical in the early stages of disease, but can appear at any time as acute liver failure.

Alpers’ Syndrome is a recessive genetic disease with a frequency of about 1:250,000 live births. Many cases die before an accurate diagnosis is made, so the true frequency is still an estimate. Alpers is caused by inheriting two copies of the POLG gene that are dysfunctional. These are called mutant copies. The function of the POLG gene is to copy mitochondrial DNA. In Alpers’ Syndrome, POLG is defective, so after a period of time, the amount of mitochondrial DNA in the cell falls below a critical threshold of about 35% of normal. When this happens, the mitochondria become sick, and begin to misfire. This leads to the brain and liver disease of classical Alpers’ Syndrome.

The cause of Alpers syndrome had remained a mystery for almost 70 years since its first description by Bernard Alpers in 1931. A number of leads over the decades failed to reveal the cause, until our 2004 paper reported thefirst two mutations in POLG linked to the disease. Within two years, the discovery of POLG involvement in Alpers syndrome was confirmed by several laboratories around the world and over 40 new causative mutations are now known. In addition, the field has grown so rapidly that we now know that mutations in POLG can cause at least seven different diseases in children and adults, with a combined disease frequency of nearly 1:10,000. As many as 1:50 people may be silent carriers of POLG mutations. Indeed, mutations in the mitochondrial DNA polymerase gamma (POLG) may be the most common single cause of inherited mitochondrial disease yet discovered. Scientifically, our 2004 paper was a compelling conclusion to our 1999 paper that showed for the first time ever, that a human disease (Alpers syndrome) was linked to a biochemical defect in a DNA polymerase (POLG). In practical terms, our discovery led directly to a rapid DNA test to diagnose Alpers syndrome. Over 80% of the cases can now be diagnosed by screening for just five common mutations. Before the advent of a DNA test, Alpers syndrome could only be confirmed by post-mortem examination. Today, doctors can diagnose the disease with a simple blood test, and prenatal diagnosis is also possible. The major problem that we encountered along the way was an absence of federal funding for our research. This discovery of POLG mutations in Alpers syndrome was funded entirely by gifts and donations from families, private foundations, and philanthropic donations. We owe a great debt to all these people who made this discovery possible with their heartfelt support and active efforts to raise public awareness for mitochondrial disease. Our immediate goals for the future of this research involve the development of a mouse model of Alpers syndrome, with the aim of better understanding the disease and developing new treatments, not only for Alperssyndrome in particular, but also for several other mitochondrial disorders that share common threads of pathogenesis. It is our hope that when these studies are merged with others in our lab, such as the use of rapid optical methods for diagnosing mitochondrial dysfunction and the role of mitochondria in wound healing and regeneration, that we will be able to develop methods for earlier diagnosis, and perhaps even reduce the risk of developing more complex disorders like diabetes, Alzheimer dementia, autoimmune disorders, heart disease, and cancer. I believe there are two important messages that come from this work. First, there is the message that grassroots support of science in America can make a difference for people that is felt around the world when government support of basic research in the life sciences falters. Second, there is the message that the blossoming of mitochondrial medicine over the past decade has announced the emergence of a fully mature new discipline in biology and medicine. Mitochondrial medicine may be the new kid on the block, but it is now clear that the health and illness of the mitochondria in our cells, critically determine our own health and our susceptibility to disease. This fundamental understanding now unites all medical specialties. The National Institutes of Health (NIH) currently have no unified infrastructure for ensuring continued support for mitochondrial disease research in America. The time is ripe—both the grassroots support and the scientific clout are present—for the initiation of United States Congressional discussions to create a new "National Institute of Mitochondrial Medicine" to ensure progress and answer the swelling need for new research in this important area ofmedicine.

An estimated 1 in 250,000 children born will have one of the most devastating mitochondrial disorders, Alper's disease. Because there are several different genetic mutations that can cause it, as many as 1 in 150 people might be at risk for having a child with Alper's. 1 in 250 people could be "silent carriers" of the genetic abnormalities that cause Alper's. There is a 50% chance that you carry one of these genes if you are related to the parent of a chld with Alper's.

Robert K. Naviaux, M.D., Ph.D.

Information provided is intended for educational purposes only and should not be construed as advising, diagnosing, or providing treatment of this or any other medical condition.